Project Summary/Abstract Dravet Spectrum disorders resulting from SCN1A loss-of-function (LOF) mutations include febrile seizures, generalized epilepsy with febrile seizure plus (GEFS+), and Dravet Syndrome (DS) in order of severity. DS symptoms begin in infancy and lead to progressive developmental and behavioral impairments along with characteristic recurrent and varied seizures. In many patients, seizures are resistant to currently available antiepileptic drugs and uncontrolled seizure activity is associated with an increased incidence of SUDEP (sudden unexplained death in epilepsy). Thus, there is a significant and urgent need for the development of novel drug therapies. SCN1A-containing Nav1.1 channels functionally oppose the related SCN8A-containing Nav1.6 channels. We have developed a novel therapeutic oligonucleotide candidate, LSP-SCN8A, that works by reducing levels of SCN8A by directing its splicing to a non-functional isoform. LSP-SCN8A greatly reduces seizures and increases lifespan in a mouse DS model. The goals of the Phase 1 portion of the study will be to perform neurophysiological characterization of LSP- SCN8A in DS mice by cellular electrophysiology and video-EEG. In the Phase 2 component, we will perform additional dose-range studies for LSP-SCN8A in DS mice, confirm splicing activity of LSP-SCN8A in human cells, and generate a PD lot of the LSP-SCN8A SMO for non-GLP dose-finding studies in juvenile rats and primates in preparation for formal GLP-toxicology studies. We will also prepare for and conduct the pre-IND meeting with the FDA. The ultimate goal of our company is to fully develop LSP-SCN8A as a therapeutic to treat DS.